Mechanisms that Govern Cardiomyocyte Proliferation and Remuscularization following Ventricular Injury

心室损伤后控制心肌细胞增殖和再肌化的机制

基本信息

  • 批准号:
    10493834
  • 负责人:
  • 金额:
    $ 238.79万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Mechanisms that govern cardiomyocyte proliferation and remuscularization following ventricular injury Program Overall The overall goal for the treatment of myocardial infarction is to replace the scar tissue caused by ischemic injury with functional cardiac muscle. Since adult mammalian cardiomyocytes (CMs) are non-proliferative, and the engraftment rate for cardiac cell therapy is extremely low, most of the remuscularizing initiatives following infarction have been unsuccessful. However, recent preliminary studies from our laboratories using neonatal pigs have shown that when myocardial infarction (MI) is induced on postnatal day 1 (P1), CMs re-enter the cell cycle, proliferate, and completely restore cardiac function with little scarring. Furthermore, we have found that these neonatal hearts with the P1 injury, have a very active and prolonged CM proliferative machinery, and consequently a second LAD ligation injury at P28, which resulted in a large infarct (TTC) at Day 2-7 post LAD ligation, produced no visible infarct 4 weeks following injury. This was a remarkable result as it demonstrated, for the first time, that a heart of large mammal could remuscularize infarcted heart tissue by CM proliferation. The studies comprising this Program Project Grant (PPG) application will examine mechanisms whereby CMs reenter the cell cycle and new strategies to remuscularize injured hearts. Project 1 will identify the CM cell-cycle regulators that are activated by MI in one-day-old pigs and construct human cardiac muscle patches (hCMP) of unprecedented clinically relevant dimensions from layers of proliferating hiPSC-CMs with activated cell cycle regulators, and other cardiac cells; subsequent experiments will determine whether the identified factors and hCMPs can remuscularize the hearts of adult pigs after MI. Project 2 will use genetic strategies, viral vectors, and modified RNAs to investigate whether members of the Sonic Hedgehog signaling pathway including Gli1 and Sox4, which have already been shown to induce proliferation in cultured CMs, will promote CM proliferation in the injured hearts of adult mice and pigs. In addition, studies will examine the capacity of the master regulator, Etv2, to promote neovascularization and promote repair of the injured hearts of adult mice and pigs. Project 3 will be an extension of previousobservations that mammalian cell-cycle arrest is at least partially induced by the increase in oxygen metabolismthat occurs after birth, and that severe systemic hypoxia upregulates proline metabolism and induces CM proliferation in adult mice; the proposed studies will examine whether proline metabolism regulates CM survivaland proliferation during chronic hypoxia. Collectively, these three projects, the associated cores and the expertise of the investigators will accelerate and amplify the studiesto address the central objective of this P01 proposal: To remuscularize the injured ventricle from “within,” by promoting endogenous CM proliferation, and from “outside,” bytransplanting functionally mature hCMPs that are primed for in-vivo CM proliferation.
摘要

项目成果

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Jianyi Zhang其他文献

Jianyi Zhang的其他文献

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{{ truncateString('Jianyi Zhang', 18)}}的其他基金

Project 1 - Endogenous and Exogenous Mechanisms that Promote Myocardial Remuscularization
项目 1 - 促进心肌再肌化的内源性和外源性机制
  • 批准号:
    10677730
  • 财政年份:
    2022
  • 资助金额:
    $ 238.79万
  • 项目类别:
Core A: Administrative Core
核心A:行政核心
  • 批准号:
    10493835
  • 财政年份:
    2022
  • 资助金额:
    $ 238.79万
  • 项目类别:
Project 1 - Endogenous and Exogenous Mechanisms that Promote Myocardial Remuscularization
项目 1 - 促进心肌再肌化的内源性和外源性机制
  • 批准号:
    10493838
  • 财政年份:
    2022
  • 资助金额:
    $ 238.79万
  • 项目类别:
Mechanisms that Govern Cardiomyocyte Proliferation and Remuscularization following Ventricular Injury
心室损伤后控制心肌细胞增殖和再肌化的机制
  • 批准号:
    10677719
  • 财政年份:
    2022
  • 资助金额:
    $ 238.79万
  • 项目类别:
Core A: Administrative Core
核心A:行政核心
  • 批准号:
    10677720
  • 财政年份:
    2022
  • 资助金额:
    $ 238.79万
  • 项目类别:
Bioenergetics in Hypertrophied and Remodeled Left Ventricle
左心室肥厚和重塑的生物能学
  • 批准号:
    8676931
  • 财政年份:
    2012
  • 资助金额:
    $ 238.79万
  • 项目类别:
Bioenergetics in Hypertrophied and Remodeled Left Ventricle
左心室肥厚和重塑的生物能学
  • 批准号:
    9162316
  • 财政年份:
    2012
  • 资助金额:
    $ 238.79万
  • 项目类别:
Endogenous and exogenous mechanisms that promote myocardial remuscularization in post infarction LV remodeling
梗死后左室重构中促进心肌再肌化的内源性和外源性机制
  • 批准号:
    10302748
  • 财政年份:
    2012
  • 资助金额:
    $ 238.79万
  • 项目类别:
Cell Therapy in Hypertrophied and Remodeled Left Ventricle
左心室肥大和重塑的细胞疗法
  • 批准号:
    9391517
  • 财政年份:
    2012
  • 资助金额:
    $ 238.79万
  • 项目类别:
Bioenergetics in Hypertrophied and Remodeled Left Ventricle
左心室肥厚和重塑的生物能学
  • 批准号:
    8528711
  • 财政年份:
    2012
  • 资助金额:
    $ 238.79万
  • 项目类别:

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